Interactions Between Nuclei and the Cytoskeleton Are Mediated by SUN-KASH Nuclear-Envelope Bridges

CB26CH17-Starr ARI 3 September 2010 19:43

Daniel A. Starr and Heidi N. Fridolfsson

Department of Molecular and Cellular Biology, University of California, Davis, California 95616; email: [email protected], [email protected]

Annu. Rev. Cell Dev. Biol. 2010. 26:421–44 Key Words First published online as a Review in Advance on nuclear positioning, outer nuclear membrane, laminopathies, May 27, 2010 microtubule motor targeting, Syne, Nesprin The Annual Review of Cell and Developmental Biology is online at cellbio.annualreviews.org Abstract This article’s doi: The nuclear envelope links the cytoskeleton to structural components 10.1146/annurev-cellbio-100109-104037 of the nucleus. It functions to coordinate nuclear migration and anchor- Copyright c 2010 by Annual Reviews. age, organize chromatin, and aid meiotic chromosome pairing. Forces All rights reserved

by University of California - Davis on 10/14/10. For personal use only. generated by the cytoskeleton are transferred across the nuclear enve- 1081-0706/10/1110-0421$20.00 lope to the nuclear lamina through a nuclear-envelope bridge consisting of SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1 and Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Syne/Nesprin homology) proteins. Some KASH-SUN combinations connect microtubules, centrosomes, actin filaments, or intermediate filaments to the surface of the nucleus. Other combinations are used in cell cycle control, nuclear import, or apoptosis. Interactions between the cytoskeleton and the nucleus also affect global cytoskeleton organization. SUN and KASH proteins were identified through genetic screens for mispositioned nuclei in model organisms. Knockouts of SUN or KASH proteins disrupt neurological and muscular development in mice. De- fects in SUN and KASH proteins have been linked to human diseases including muscular dystrophy, ataxia, progeria, lissencephaly, and cancer.

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Contents Attachment of Nuclei to INTRODUCTION...... 422 Intermediate Filaments ...... 430 DISCOVERY OF KASH KASH AND SUN PROTEINS AND SUN PROTEINS AND REGULATE THE GLOBAL THE FORMATION OF THE CYTOSKELETON ...... 431 NUCLEAR-ENVELOPE FUNCTIONS OF KASH-SUN BRIDGE...... 423 BRIDGES IN MEIOTIC Discovery of SUN Proteins ...... 423 CHROMOSOME SUN Proteins Constitute the MOVEMENTS...... 431 Inner Nuclear Membrane Half OTHER FUNCTIONS OF KASH of the Nuclear-Envelope ANDSUNPROTEINS...... 432 Bridge ...... 423 C. elegans KDP-1 Regulates the Discovery of KASH Proteins...... 425 Progression of the Cell Cycle . . 432 KASH Proteins Interact WIPs Recruit RanGAP with SUN Proteins to Complete to the Outer Nuclear the Nuclear-Envelope Bridge . . 427 Membrane...... 433 FUNCTIONS OF KASH Recruitment of CED-4 to the PROTEINS AT THE OUTER Nuclear Envelope to Mediate NUCLEAR MEMBRANE IN Apoptosis ...... 433 POSITIONING NUCLEI ...... 428 FUNCTIONS OF KASH-SUN Anchoring Nuclei to the Actin PROTEINS IN MAMMALS: Cytoskeleton...... 428 MOUSE MODELS AND Centrosome Attachment to the HUMANDISEASES...... 433 Nuclear Envelope during Nuclear Positioning in Muscles PronuclearMigration...... 428 and Muscular Dystrophies . . . . . 433 Nuclear Anchorage to Neuronal Functions of Microtubules through Dynein. . 429 SUN-KASH Proteins ...... 435 Targeting and Coordination of SUN-KASH Proteins in Aging. . . . 436 Kinesin-1 and Dynein at the SUN-KASH Proteins in Skin NuclearSurface...... 430 Development, Ciliogenesis, andCancer...... 436 by University of California - Davis on 10/14/10. For personal use only.

Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org INTRODUCTION the nucleus interacts with the cytoskeleton, how The nuclear envelope is a specialized exten- forces are transferred across the nuclear enve- sion of the endoplasmic reticulum (ER) that lope, and how these processes relate to human compartmentalizes the genome. It also pro- disease. vides physical rigidity to the nucleus, organizes The nuclear envelope consists of two par- chromatin, functions in meiotic chromosome allel membranes, the inner nuclear mem- ER: endoplasmic pairing, and positions the nucleus within the brane (INM) and outer nuclear membrane reticulum cell. Interactions between the cytoskeleton and (ONM), that are contiguous at the nuclear pore INM: inner nuclear the nuclear envelope are central to all of these (Figure 1a). The ONM is also contiguous membrane functions. The same molecular mechanisms are with the ER (reviewed in Franke et al. 1981). ONM: outer nuclear used in these processes to transfer forces gener- The membranes of the nuclear envelope are membrane ated in the cytoskeleton to the structural com- supported by the nuclear lamina that imme- ponents inside the nucleus. Here we review how diately underlies the INM. In metazoans, the

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lamina consists of membrane proteins, the ab intermediate ﬁlament lamin, and proteins as- ER sociated with chromatin (reviewed in Gruen- baum et al. 2005). To form a nuclear-envelope bridge, membrane proteins are trafﬁcked from the ER membrane either to the INM to interact SUN KASH with the lamina, or to the ONM to interact with protein protein the cytoskeleton. To complete the bridge, INM and ONM proteins interact with each other in the perinuclear space. The current KASH- NPC SUN nuclear-envelope bridging model, also referred to as the linker of nucleoskeleton and cytoskeleton (LINC) complex model, posits that SUN (Sad1 and UNC-84) proteins in the INM INM ONM interact with KASH (Klarsicht, ANC-1, and

Syne/Nesprin homology) proteins of the ONM Cytoplasm to span the nuclear envelope (Figure 1b). Nucleus DISCOVERY OF KASH AND SUN PROTEINS AND 0.2 μm THE FORMATION OF THE Figure 1 NUCLEAR-ENVELOPE BRIDGE Klarsicht, ANC-1, and Syne/Nesprin homology (KASH) and Sad1 and UNC-84 (SUN) proteins bridge the two membranes of the nuclear envelope. Discovery of SUN Proteins (a) A transmission electron microscopy (TEM) image and (b) a schematic representation of the nuclear envelope in an amphibian oocyte showing how Our current understanding of the molecu- the inner nuclear membrane (INM), outer nuclear membrane (ONM), and lar mechanisms of the SUN-KASH nuclear- endoplasmic reticulum (ER) are contiguous. NPC, nuclear pore complex. A envelope bridge is based on characterizations generic SUN and KASH protein bridge is drawn with conserved SUN (red ) of genetic mutants in Caenorhabditis elegans and KASH (purple) domains in the perinuclear space of the nuclear envelope. TEM image reproduced with permission from J. Cell Biol. (Franke et al. 1981). and Drosophila with mispositioned nuclei (reviewed in Starr & Fischer 2005, Starr & Han termed the SUN domain (Malone et al. 1999). 2005, Wilhelmsen et al. 2006). SUN proteins Sad1 is an essential component of the spindle were discovered by molecular analysis of C. pole body required for normal spindle archi- elegans unc-84. Alleles of unc-84 were orig-

by University of California - Davis on 10/14/10. For personal use only. tecture (Hagan & Yanmagida 1995). Overex- inally isolated because of their defects in P pressed Sad1::green ﬂuorescent protein (GFP) cell nuclear migration, which results in miss- accumulates at the nuclear envelope, suggest-

Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org ing neurons and vulval cells, leading to unco- ing an additional role for Sad1 in nuclear posi- ordinated and egg-laying defective phenotypes tioning during interphase (Goshima et al. 1999, Nuclear-envelope (Figure 2a, Horvitz & Sulston 1980, Sulston bridge: a complex of Tran et al. 2001). UNC-84 also localizes to the & Horvitz 1981). unc-84 alleles also cause nu- SUN proteins at the nuclear envelope (Lee et al. 2002, Malone et al. clear migration defects in epidermal precursors INM and KASH 1999). Proteins with SUN domains are referred proteins at the ONM (Figure 2b, Horvitz & Sulston 1980, Sulston to as SUN proteins and localize to the INM. that transfer forces & Horvitz 1981). The molecular cloning of generated in the UNC-84 (Malone et al. 1999) in effect founded cytoplasm to the the SUN-KASH ﬁeld. SUN Proteins Constitute the nuclear lamina The C terminus of UNC-84 was found to Inner Nuclear Membrane Half LINC: linker of be conserved with the C termini of Schizosac- of the Nuclear-Envelope Bridge nucleoskeleton and charomyces pombe Sad1 and two human pro- SUN proteins are conserved across eukary- cytoskeleton teins; each contains a ∼175 amino acid domain otes including fungi, plants, animals, and basal

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a P cell nuclear migration in C. elegans larvae b Nuclear migration in C. elegans embryo Wild type Wild type

Ventral cord Forms vulva and neurons unc-83 or unc-84 unc-83 or unc-84

Egl and Unc Dorsal cord animals

c Nuclear migration in Drosophila eye disc d Nuclear achorage in C. elegans syncytia Wild type klarsicht or klaroid Wild type

Apical

anc-1 or unc-84

Basal

Figure 2 Genetic models for studying nuclear positioning. (a) Nuclear migration in hypodermal P cells during the ﬁrst larval stage of Caenorhabditis elegans. Nuclei (dark blue) migrate from a lateral to a ventral position through the cytoplasm (light blue). P cells normally go on to form the vulva and neurons in the ventral cord. Mutations in unc-83 or unc-84 disrupt nuclear migration and the P cells die, resulting in egg-laying defective (Egl) and uncoordinated (Unc) animals. (b) Nuclear migration in C. elegans embryonic hypodermal cells. Right (light blue)andleft(light green) hyp7 precursors align along the dorsal cord of a pre-elongation embryo (brown circle, dorsal view, anterior to the left) and intercalate to form a row of column-shaped cells spanning the dorsal midline. Nuclei (dark blue and dark green) then migrate the length of the cell from right to left (blue) or left to right (green). Mutations in unc-83 and unc-84 disrupt nuclear migration, and all nuclei end up in the dorsal cord instead of their normal, lateral positions. (c) Nuclear migration in the Drosophila eye

by University of California - Davis on 10/14/10. For personal use only. disc. After the morphogenetic furrow passes, nuclei (dark blue) migrate from a basal position to an apical one as they develop into photoreceptors. In klarsicht or klaroid mutants, nuclei abnormally remain basal, disrupting the development of the eye, whereas centrosomes (black ovals) organize microtubules (red strands) from an apical position. (d ) Nuclear anchorage in the adult C. elegans

Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org syncytial hypodermis. Three large hypodermal syncytia, the hyp7 (light blue) syncytium and the lateral seam-cell syncytia (light green), are used to study nuclear anchorage. Normally nuclei (dark blue and dark green) are anchored and spaced evenly apart. In anc-1 or unc-84 mutant animals, nuclei are unanchored and often associate in clusters.

eukaryotes such as Giardia (Graumann et al. Malone et al. 2003, Padmakumar et al. 2005, 2009, Jaspersen et al. 2006, Malone et al. 1999, Shao et al. 1999). SUN proteins have many Mans et al. 2004, Starr 2009). Many higher common features. They have at least one trans- Sad1 and UNC-84 (SUN) domain: a eukaryotes have multiple SUN proteins that membrane domain that enables most to local- conserved domain of are often expressed at different times in devel- ize in the nuclear membrane (reviewed in Starr an INM protein that opment (Crisp et al. 2006, Ding et al. 2007, 2009, Tzur et al. 2006b, Worman & Gundersen recruits KASH Graumann et al. 2009, Hodzic et al. 2004, 2006). Speciﬁcally, data suggest that SUN pro- proteins to the ONM Kracklauer et al. 2007, Lu et al. 2008, teins are components of the INM with the SUN

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domain in the perinuclear space (Chikashige Discovery of KASH Proteins et al. 2006, Crisp et al. 2006, Haque et al. 2006, Drosophila Klarsicht, C. elegans ANC-1, and the Hodzic et al. 2004, Jaspersen et al. 2002, McGee mammalian paralogs Syne/Nesprin-1 and -2 Klarsicht, ANC-1, et al. 2006, Padmakumar et al. 2005). Most are the founding KASH (Klarsicht, ANC-1, and Syne homology SUN proteins contain short coiled-coil regions and Syne homology) proteins. The molecular (KASH) domain: a in their perinuclear domains that aid in dimer- transmembrane span cloning of ANC-1 led to the recognition that ization or multimerization (Crisp et al. 2006, followed by 6–30 all of these proteins contain a conserved C- Haque et al. 2006, Lu et al. 2008, Malone et al. residues at the C terminal KASH domain (Starr & Han 2002). terminus of a protein 1999). Mutations in Drosophila klarsicht (originally that targets proteins to The nucleoplasmic domains of SUN pro- called marbles) were isolated in screens for the ONM teins are not conserved. Although the N- eye morphogenesis defects (Fischer-Vize & Nuclear positioning: terminal nucleoplasmic domains contain the Mosley 1994). Normally nuclei migrate basally the act of a nucleus signals needed for nuclear envelope localiza- migrating to a speciﬁc in the pseudostratiﬁed neuroepithelium of the tion, how they are targeted to the nucleo- location within a cell developing eye disc before migrating apically plasm is not understood (Haque et al. 2010, and the process used to to differentiate (Tomlinson 1985). In klarsicht anchor it there Hasan et al. 2006, Hodzic et al. 2004). Some mutant animals, nuclei remain basal although SUN proteins contain classical nuclear local- Microtubule motors: centrosomes are in their normal apical posi- ATPases that move ization signals, but mutating the mammalian tion (Figure 2c, Fischer-Vize & Mosley 1994, cargo along Sun1 classical nuclear localization signal has no Mosley-Bishop et al. 1999, Patterson et al. microtubule tracks; effect on nuclear envelope localization (Hodzic dynein moves toward 2004). Klarsicht localization to the nuclear en- et al. 2004). Other SUN proteins have predicted the minus ends and velope requires lamin and the SUN protein INM-sorting motifs (Braunagel et al. 2004), kinesin-1 toward the Klaroid (Kracklauer et al. 2007, Patterson et al. plus ends but their function in targeting to the INM re- 2004). Klarsicht has been proposed to coordi- mains to be determined. Many SUN proteins nate the activity of microtubule motors during interact with lamins, but only some SUN pronuclear migration (Figure 3c; Patterson et al. teins require a functional lamin for localization 2004, Welte 2004, Welte et al. 1998). (Fridkin et al. 2004; Haque et al. 2006, 2010; Once a nucleus migrates to the proper po- Hasan et al. 2006; Lee et al. 2002). Once in sition in the cell, mechanisms must exist to an- the nucleoplasm, the N termini of SUN pro- chor it in place. Most of an adult C. elegans teins likely interact with the lamina or chro- is covered with four large hypodermal syncy- matin and have been hypothesized to regulate tia containing more than 100 nuclei in total. gene expression (Chi et al. 2007, King et al. Normally these nuclei are evenly spaced and 2008, Oza et al. 2009, Wang et al. 2009). In anchored in place. However, in anc-1 or unc-

by University of California - Davis on 10/14/10. For personal use only. S. pombe, which has no lamins, the SUN pro- 84 mutant animals, nuclei ﬂoat freely in the tein Sad1 interacts with centromeres and het- cytoplasm, often associating in large clusters erochromatin in a network that is stabilized (Figures 2d and 4a, Hedgecock & Thomson Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org by the INM protein Ima1 (NET5, for nuclear 1982, Malone et al. 1999). ANC-1 is a gi- envelope targeted, in mammals) (King et al. ant protein of more than 8500 residues with 2008). homology to Drosophila MSP-300, a protein The evidence supports a model in which required for muscle development, and mam- SUN proteins form the INM half of a nuclear- malian Syne/Nesprin-1 and -2 (Starr & Han envelope bridge (Figures 1 and 3). In this role, 2002). Like Klarsicht, ANC-1 localizes to the SUN proteins anchor the bridge to the nuclear nuclear envelope via a SUN protein, UNC-84 lamina. Central to this model is that SUN pro- (Starr & Han 2002). teins also recruit the second half of the bridge, Mammalian Syne/Nesprin-1 was ﬁrst KASH proteins, to the ONM. cloned as a component of the postsynaptic

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Actin filaments

ANC-1 MSP-300 Syne/Nesprin-1 and 2

Microtubules Intermediate filaments Centrosome

Kinesin-1

Dynein Plectin BicD Cell cycle NudE/Lis1 Actin progression KLC Dynein Cytoplasm ? UNC-83 ZYG-12 Kms1/2 Nesprin-3 Nesprin-4 Klar Csm4 ER ONM KDP-1 KASH INM SUN SUN-1 Klaroid Sad1 Pore UNC-84 UNC-84 Mps3 Dm SUN Hs SUN Telomere Hs SUN Hs SUN abcd e f gSUN-1 h UNC-84? Lamin Nucleus

Figure 3 Functions of KASH-SUN nuclear-envelope bridges. KASH proteins are in the outer nuclear membrane (ONM). SUN protein dimers (gold circles) are located in the inner nuclear membrane (INM) with their SUN domains (red ) in the perinuclear space, where they interact with KASH domains (purple) to bridge the nuclear envelope. (a) Giant KASH proteins (blue) tether nuclei to actin filaments (green). (b) UNC-83 and Nesprin-4 (green) function as nucleus-specific cargo adaptors for microtubule motors kinesin-1 (red ) through the kinesin light chain (KLC, dark red ) and, at least for UNC-83, dynein (teal) through BicD and NudE/Lis1 complexes (pink and purple). (c) Klarsicht (Klar, green) is thought to interact with dynein for nuclear migration. (d-f ) Nucleoplasmic domains of SUN by University of California - Davis on 10/14/10. For personal use only. proteins interact with meiotic chromosomes (gray lines) through adaptors (gray circles) to aid in proper homolog pairing. (d )Worm ZYG-12 (orange) interacts with a KASH-less isoform of itself and dynein to tether the centrosome to the nucleus, to position the nucleus, and to move chromosomes in meiosis. (e) Fission yeast Kms1 and 2 (blue) recruit dynein to move nuclei and telomeres in Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org meiosis. (f) Budding yeast Csm4 (blue) links actin filaments to the nucleus to move telomeres through unknown intermediates (?). (g) Nesprin-3 interacts with intermediate filaments (gray) through plectin (blue). (h) Worm KDP-1 promotes cell-cycle progression. Dm, Drosophila melanogaster; Hs, Homo sapiens.

apparatus in the neuromuscular junction termed Nesprin (nuclear envelope spectrin as a two-hybrid interacting partner of the repeat) (Zhang et al. 2001), as novel spectrin muscle-speciﬁc receptor tyrosine kinase repeat-containing proteins called Myne (my- (MuSK) and named Syne-1 (synaptic nuclear ocyte nuclear envelope) (Mislow et al. 2002b), envelope-1) (Apel et al. 2000). Subsequently, by homology to C. elegans ANC-1 (Starr Syne/Nesprin-1 and/or -2 were isolated as & Han 2002), as a Golgi complex–speciﬁc markers of vascular smooth muscle cells and spectrin protein (Gough et al. 2003), and

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as a plasticity-related protein called CPG2 (Cottrell et al. 2004). The giant, full-length CP Syne/Nesprin-1 and -2 transcripts (Enaptin and NUANCE) were identified by their IZ N-terminal actin-binding domains having similarity to α-actinin (Padmakumar et al. abc 2004, Zhen et al. 2002). Multiple antibodies against Syne/Nesprin-1 and -2 localize to the IZ nuclear envelope (Apel et al. 2000, Mislow et al. 2002b, Zhang et al. 2001, Zhang et al. 2007b, Zhen et al. 2002), and this localization is dependent on SUN proteins (Crisp et al. a' b' c' 2006, Lei et al. 2009, Padmakumar et al. 2005). 15 μm 15 μm 250 μm Figure 4 ANC-1 and Syne/Nesprin-1 and -2 tether nuclei to the actin cytoskeleton. (a) In wild-type adult C. elegans, large syncytial nuclei [green fluorescent protein KASH Proteins Interact (GFP) positive] are evenly spaced. (a )Inananc-1 mutant animal, nuclei are with SUN Proteins to Complete unanchored and are pushed around by underlying tissues and frequently cluster the Nuclear-Envelope Bridge together. (b) A mouse neuromuscular junction (NMJ) (red )froma heterozygous control with four muscle nuclei (green) clustered underneath. KASH proteins have multiple common features (b ) In a Syne/Nesprin-1 KASH knockout mouse, nuclei fail to anchor (reviewed in Starr & Fischer 2005). First, they underneath the NMJ. Reproduced with permission from Development (Zhang contain a C-terminal conserved KASH domain et al. 2007b). (c) A coronal section of an E18.5 heterozygous control mouse consisting of a membrane-spanning region fol- showing neuronal migration. Green cells were transfected with a GFP construct at E14.5. In that time, neurons migrated through the intermediate lowed by fewer than 35 residues before the C zone (IZ) to the cortical plate (CP). (c ) In an analogously prepared slice of a terminus. The KASH domains of the founding Syne/Nesprin-1 and -2 homozygous double KASH knockout brain, most members of the family are highly similar, but nuclear migrations failed. Adapted with permission from Neuron (Zhang et al. other, more distantly related KASH domains 2009). have been identified (McGee et al. 2009, Starr 2009). KASH proteins are likely tail-anchored A valuable tool for studying KASH proteins proteins inserted into the ER membrane post- is a dominant-negative construct overex- translationally by Asna1-GET3 (Mateja et al. pressing a KASH domain. When the ANC-1 2009, Rabu et al. 2009, Schuldiner et al. 2008, KASH domain is overexpressed in C. elegans, Stefanovic & Hegde 2007). Second, KASH endogenous ANC-1 is displaced from the nuclear envelope, causing a strong nuclear by University of California - Davis on 10/14/10. For personal use only. proteins localize to the ONM with their conserved KASH domain inserted into the per- positioning phenotype (Starr & Han 2002). inuclear lumen and their large, divergent N- Analogous approaches have been used to study Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org terminal domains in the cytoplasm. A KASH vertebrate Syne/Nesprin-1 and -2 (Grady domain is necessary and sufficient to target et al. 2005, Tsujikawa et al. 2007). However, a protein to the ONM (Fischer et al. 2004, the approach is nonspecific, and all KASH Grady et al. 2005, Guo et al. 2005, McGee proteins are likely displaced from the ONM, et al. 2006, Meyerzon et al. 2009a, Starr & which makes it difficult to assign the resulting Han 2002, Zhang et al. 2001, Zhang et al. phenotypes to a single KASH protein. 2007b). All known integral membrane pro- Central to the nuclear-envelope bridge teins that localize specifically to the ONM are model is that KASH proteins require SUN KASH proteins (Figure 3 and Supplemental proteins for localization to the ONM (Crisp Table 1; follow the Supplemental Material et al. 2006, Lei et al. 2009, Padmakumar et al. link from the Annual Reviews home page at 2005, Starr & Han 2002). In support of this http://www.annualreviews.org). genetic requirement, KASH and SUN domains

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directly interact (Crisp et al. 2006, Haque et al. Zhen et al. 2002). Finally, they have extended 2010, McGee et al. 2006, Minn et al. 2009, middle domains that at least in the cases of Ostlund et al. 2009, Padmakumar et al. 2005, MSP-300 and Syne/Nesprin-1 and -2 are re- Stewart-Hutchinson et al. 2008). Once the lated to spectrin, making these proteins related nuclear-envelope bridge is formed, the diver- to dystrophin (Starr & Han 2003). gent cytoplasmic domains of KASH proteins Phenotypic analyses demonstrate that C. el- are localized to the outer surface of the nuclear egans ANC-1 and mouse Syne/Nesprin-1 and envelope, where they perform a variety of -2 anchor nuclei within the cell (Figure 4a,b; functions. Starr & Han 2002, Zhang et al. 2007b). The KASH-SUN interactions are dynamic. For role of MSP-300 in nuclear anchorage is not example, the SUN protein UNC-84 functions clear (Technau & Roth 2008, Xie & Fischer with the KASH protein ANC-1 during nuclear 2008, Yu et al. 2006). These large KASH pro- anchorage, but then functions through UNC- teins are thought to function as ropes, extending 83 during nuclear migration (Starr & Han 2002, away from the nuclear envelope to tether actin Starr et al. 2001). The best candidate for a reg- filaments to the ONM (Figure 3a). An alter- ulator of KASH-SUN interactions is the chap- native hypothesis is that Syne/Nesprin-1 and eronin TorsinA (Naismith et al. 2004). TorsinA -2 form a spectrin-like filamentous basket sur- localizes to the ER and perinuclear lumens rounding and supporting the ONM (Schneider and physically interacts with KASH domains et al. 2008). (Goodchild & Dauer 2004, Nery et al. 2008). Furthermore, changing the amount of TorsinA at the nuclear envelope displaces KASH-SUN Centrosome Attachment to the complexes and alters the structure of the nu- Nuclear Envelope during clear envelope (Naismith et al. 2004, Nery et al. Pronuclear Migration 2008, Vander Heyden et al. 2009). In most cells, at least during part of the cell cycle, centrosomes are closely associated with the nuclear envelope (Bornens 1977, Starr 2009). FUNCTIONS OF KASH PROTEINS However, little is known about how this in- AT THE OUTER NUCLEAR teraction is maintained. The KASH protein MEMBRANE IN POSITIONING ZYG-12 and the SUN protein SUN-1/matefin NUCLEI are essential for pronuclear migration in C. elegans. Normally the female pronucleus mi- Anchoring Nuclei to the grates toward the male pronucleus along mi- Actin Cytoskeleton

by University of California - Davis on 10/14/10. For personal use only. crotubules emanating from centrosomes that The giant proteins C. elegans ANC-1 (8546 are closely associated with the male pronucleus residues for the largest predicted isoform), (Reinsch & Gonczy 1998). Mutations in zyg-12, Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Drosophila MSP-300 (8204), and mammalian originally isolated as a zygotic lethal mutation Syne/Nesprin-1 and -2 (8739 and 6885) are or- (Wood et al. 1980), or sun-1/matefin, as found thologs (Starr & Han 2002, Zhang et al. 2002). in a genome-wide RNAi screen, disrupt cen- Dictyostelium Interaptin, although smaller and trosome attachment to the nuclear envelope, less similar, might also be an ortholog (Rivero blocking pronuclear migration (Figure 5a, et al. 1998). All of them contain a highly sim- Malone et al. 2003). ilar C-terminal KASH domain that is suffi- ZYG-12 is a KASH protein with an N- cient for targeting to the ONM (Starr & Han terminal cytoplasmic domain similar to that 2002, Yu et al. 2006, Zhang et al. 2001). Addi- of Hook proteins (Malone et al. 2003), which tionally, their N termini are homologous with are hypothesized to link membrane compart- calponin, bind actin in vitro, and colocalize with ments to microtubules (Walenta et al. 2001). actin filaments (Starr & Han 2002, Volk 1992, SUN-1/matefin recruits ZYG-12 to the ONM

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abc

a' b' c'

10 μm 25 μm 10 μm

Figure 5 Functions of ZYG-1 and SUN-1/mateﬁn. (a) A wild-type one-cell C. elegans embryo expressing GFP::tubulin. The male and female pronuclei (dark holes in background) have completed their migration, and both centrosomes remain closely attached to the male pronucleus. (a )Inazyg-12 mutant embryo, the centrosomes fail to attach to the male pronucleus, and pronuclear migration fails. Reproduced with permission from Cell (Malone et al. 2003). (b) The midsection of a wild-type adult C. elegans syncytial gonad is shown. ZYG-12 (green) marks the nuclear envelope, and tubulin is shown in red. Nuclei are anchored at the periphery of the syncytial gonad. (b )Inazyg-12(ct350) mutant, nuclei fall into the center of the syncytial gonad. Reproduced with permission from The Journal of Cell Biology (Zhou et al. 2009). (c)CED-4(green)is recruited to the nuclear envelope (rings)inaC. elegans embryo. (c ) In a similarly staged sun-1/mtf-1 mutant embryo, CED-4 fails to be recruited to the nuclear envelope. Reproduced with permission from the Proceedings of the National Academy of Sciences, U.S.A. (Tzur et al. 2006).

(Malone et al. 2003, Minn et al. 2009), where for centrosome attachment during nuclear it interacts with the dynein light-intermediate migration events later in C. elegans development chain DLI-1 to recruit dynein heavy chain to (Lee et al. 2002, Starr et al. 2001). However, the cytoplasmic surface of the nuclear envelope in Dictyostelium, a SUN protein is required for (Malone et al. 2003). This allows the grow- centrosome attachment (Xiong et al. 2008), and ing male pronucleus to quickly recapture mi- mouse Syne/Nesprin-1 and -2 double knock-

by University of California - Davis on 10/14/10. For personal use only. crotubule asters that might have drifted away out cells have a centrosome detachment pheno- from it (Malone et al. 2003, Meyerzon et al. type (Zhang et al. 2009). Other nuclear enve- 2009b). However, disruption of dynein heavy lope components including emerin and lamin Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org chain by RNAi causes only approximately 15% attach centrosomes to nuclei in tissue culture of centrosomes to be detached from the male ﬁbroblasts (Lee et al. 2007, Salpingidou et al. pronucleus (Gonczy et al. 1999). To com- 2007). pletely attach the centrosome to the nuclear envelope, ZYG-12 in the ONM interacts with a KASH-less isoform of ZYG-12 indepen- Nuclear Anchorage to dently recruited to the centrosome (Figure 3d, Microtubules through Dynein Malone et al. 2003). Nuclei are in an orderly arrangement at the In other tissues and systems, the role of periphery of the syncytial C. elegans gonad KASH-SUN bridges in centrosome attach- (Hubbard & Greenstein 2005). ZYG-12 and ment to the nucleus is less clear. For exam- SUN-1/mateﬁn are required to maintain ple, KASH and SUN proteins are not required the even spacing of nuclei and to prevent

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them from falling into the nucleus-free center neuroepithelium, suggesting that different of the syncytial gonad via, surprisingly, a KASH proteins play similar functions in centrosome-independent process (Zhou et al. different tissues (Zhang et al. 2009). Drosophila 2009). Both zyg-12 alleles, zyg-12(ct350) and Klarsicht has also been proposed to function zyg-12(or577), disrupt centrosome attachment through kinesin-1 (Shubeita et al. 2008, Welte during pronuclear migration, but only the et al. 1998). Although they do not contain any zyg-12(ct350) allele disrupts nuclear posi- stretches of obvious similarity outside of their tioning in the gonad (Figure 5b,Zhouetal. KASH domains, UNC-83, Nesprin-4, and 2009). The zyg-12(ct350) allele disrupts the Klarsicht may be functional homologs. All of ZYG-12-DLI-1 interaction and ZYG-12 them appear to function as cargo adaptors at dimerization, whereas the zyg-12(or577) allele the nuclear envelope to recruit kinesin-1 to disrupts only dimerization (Malone et al. 2003, the cytoplasmic face of the nucleus (Figure 3b, Zhou et al. 2009). Therefore, ZYG-12 is Meyerzon et al. 2009a, Roux et al. 2009). In hypothesized to function through dynein, but support of this model, a hybrid KLC-2::KASH not the centrosome, to anchor nuclei to micro- construct effectively targets to the ONM in tubules in the gonad (Zhou et al. 2009). The transgenic C. elegans and rescues the unc-83 extent to which this mechanism is conserved nuclear migration defect (Meyerzon et al. in other tissues and organisms remains to be 2009a). determined. UNC-83 also interacts with two dynein- regulating complexes (Fridolfsson et al. 2010). Mutations in any of these components or in Targeting and Coordination of dynein heavy chain cause nuclear migration de- Kinesin-1 and Dynein at the fects. The defects are much less severe than unc- Nuclear Surface 83 or kinesin-1 mutants, suggesting that dynein The KASH protein UNC-83 and the SUN plays a regulatory role in hypodermal nuclear protein UNC-84 function together during nu- migration (Fridolfsson et al. 2010). We pro- clear migration in a variety of C. elegans tissues pose that UNC-83 is a nuclear-speciﬁc cargo (Figure 2, Malone et al. 1999, Starr et al. 2001). adaptor for both motors and functions to co- The mechanisms through which UNC-83 ordinate bidirectional movements leading to a generates forces to move nuclei were recently net migration toward the plus ends of micro- elucidated. The cytoplasmic domain of UNC- tubules (Figure 3b). Whereas kinesin-1 pro- 83 binds the KLC-2 light chain of kinesin-1 and vides the major force, dynein ensures that the three regulators of dynein (Fridolfsson et al. migration proceeds normally (Fridolfsson et al.

by University of California - Davis on 10/14/10. For personal use only. 2010, Meyerzon et al. 2009a). Kinesin-1 mutant 2010). animals have severe nuclear migration defects (Meyerzon et al. 2009a). Similarly, mammalian Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Nesprin-4 interacts with kinesin light chain Attachment of Nuclei (Roux et al. 2009). Nesprin-4 expression is to Intermediate Filaments limited to secretory endrocrine cells, making it Intermediate filaments have long been pro- difficult to study its role in nuclear migration posed to play a role in nuclear positioning. (Roux et al. 2009). However, when expressed Vimentin is often associated with nuclei, and in a heterologous HeLa system, Nesprin-4 defects in vimentin disrupt nuclear morphol- recruits kinesin-1 to the nuclear envelope and ogy (Toivola et al. 2005). Additionally, mice induces the nucleus to move away from the with knockouts of desmin have severe nuclear centrosome toward the plus ends of micro- anchorage defects in skeletal muscles (Ralston tubules, suggesting that it plays a role in nuclear et al. 2006). Thus, it is not surprising that a positioning (Roux et al. 2009). Syne/Nesprin-2 KASH protein associates with intermediate interacts with dynein and kinesin in the filaments (Figure 3g). Plectin is a plakin family

430 Starr · Fridolfsson CB26CH17-Starr ARI 3 September 2010 19:43

member that cross-links actin filaments to FUNCTIONS OF KASH-SUN intermediate filaments (Wiche 1998). A yeast BRIDGES IN MEIOTIC two-hybrid screen with the actin-binding do- CHROMOSOME MOVEMENTS main of plectin identified the N terminus of the The initial characterization of KASH-SUN KASH protein Nesprin-3 (Wilhelmsen et al. bridges came from studying their roles in the 2005). The KASH domain of Nesprin-3 and positioning of whole nuclei. Another interest- Sun1 and/or Sun2 are necessary for localiza- ing problem is how forces generated in the cy- tion of Nesprin-3 to the ONM (Ketema et al. toskeleton are used to move objects within the 2007). Overexpression of Nesprin-3 recruits nucleus. A major discovery in the field was the intermediate filaments to the nuclear envelope demonstration that KASH-SUN bridges are (Wilhelmsen et al. 2005). However, a mouse also used to move telomeres within the nucleus knockout of Nesprin-3 has no obvious mor- during meiosis in S. pombe (Figures 3e and 6c; phological phenotypes (K. Lei and R. Xu, Chikashige et al. 2006). personal communication). Thus, the role of In many systems, meiotic chromosomes Nesprin-3 in nuclear positioning remains to dramatically rearrange such that telomeres be characterized. associate with the INM and cluster together to form a bouquet, which aids in homolog pairing (reviewed in Harper et al. 2004). The forces to KASH AND SUN PROTEINS move meiotic chromosomes are generated by REGULATE THE GLOBAL dynein on microtubules in S. pombe and C. ele- CYTOSKELETON gans (Figure 3d,e; Chikashige et al. 2006, Sato ANC-1 and Syne/Nesprin-1 and -2 have addi- et al. 2009) but by actin dynamics in Saccha- tional functions in the regulation of the global romyces cerevisiae (Figure 3f, Conrad et al. 2008, cytoskeleton and subsequent localization of Koszul et al. 2008). KASH-SUN bridges then other organelles. For example, anc-1 mutant transfer these forces across the nuclear enve- animals have a mitochondrial positioning lope to the meiotic chromosomes (reviewed in defect (Hedgecock & Thomson 1982, Starr & Hiraoka & Dernburg 2009, Starr 2009). SUN Han 2002). Syne/Nesprin-1 plays roles in the proteins are required for the association of structure of the Golgi complex, cytokinesis, telomeres (or pairing centers in C. elegans)tothe formation of a perinuclear actin cap, and INM (Figure 6, Bupp et al. 2007, Conrad et al. vesicle transport (Fan & Beck 2004, Gough 2007, Ding et al. 2007, Penkner et al. 2007). & Beck 2004, Gough et al. 2003, Khatau KASH proteins Kms1 and Kms2 in S. pombe et al. 2009). In dominant-negative KASH and ZYG-12 in C. elegans interact with dynein

by University of California - Davis on 10/14/10. For personal use only. overexpression 3T3 cells, the mechanical to move along microtubules (Chikashige et al. stiffness of the cytoskeleton far away from the 2006, Miki et al. 2004, Penkner et al. 2009, Sato nucleus is disrupted (Stewart-Hutchinson et al. et al. 2009). The S. cerevisiae KASH protein Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org 2008). Additionally, mechanically pulling on Csm4 interacts with the actin cytoskeleton beads attached to the surfaces of cells through (Conrad et al. 2008, Koszul et al. 2008, Starr integrins causes immediate reorganization of 2009). Defects in the KASH or SUN proteins the nucleoplasm, suggesting that the extra- involved in meiotic chromosome movements cellular matrix is physically connected to the lead to aberrant synapsis and a reduction in nucleoplasm (Maniotis et al. 1997). These data recombination, but do not block recombina- lead to a hypothesis that KASH and SUN tion (reviewed in Hiraoka & Dernburg 2009, proteins function in mechanotransduction of Koszul & Kleckner 2009). physical signals from the extracellular matrix The ﬁnding that KASH-SUN bridges are directly to chromatin ( Jaalouk & Lammerding used to move meiotic chromosomes opens up 2009, Wang et al. 2009). the question as to what their role might be

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100 μm 2 μm a c ChCh

NucleusNucleus

Telo

NENE CytoplasmCytoplasm

bb' Sad1

Merged

10 μm 89 109 139 180 Time (min)

Figure 6 Roles of KASH-SUN bridges in moving meiotic chromosomes. (a) Transmission electron microscopy image from a mouse spermatocyte showing a telomere (arrowheads) of a synapsed meiotic bivalent (extending up from telomere) attached to the inner nuclear membrane (INM) of the nuclear envelope (NE). Ch, chromatin. Reproduced with permission from The Proceedings of the National Academy of Sciences, U.S.A. (Schmitt et al. 2007). (b) A heterozygous control mouse spermatocyte showing telomeres (red ) of bivalents (green) attached to the nuclear envelope (purple). (b ) A spermatoycyte from a sterile Sun1 homozygous knockout mouse showing that telomeres fail to attach to the nuclear envelope. Reproduced with permission from Developmental Cell (Ding et al. 2007). (c)Sad1(red in merge) localizes predominantly to the spindle pole body (89 min). During meiosis, some Sad1 leaves the spindle pole body, associates with telomeres (Telo, green in merge) on the INM (109 min), and moves the telomeres to the spindle pole body to form the bouquet formation (180 min). Reproduced with permission from Cell (Chikashige et al. 2006).

in chromosome movements in interphase cells. forces generated in the cytoplasm to the struc- Moving loci within the nucleoplasm affects tural components of the nucleus. Other KASH

by University of California - Davis on 10/14/10. For personal use only. transcription (reviewed in Akhtar & Gasser proteins recruited to the ONM are used to reg- 2007). Therefore, and in agreement with the ulate diverse cellular processes. mechanotransduction hypothesis, KASH and Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org SUN proteins are likely to play active roles in transcription control. In one example, the S. C. elegans KDP-1 Regulates the pombe KASH proteins Kms1 and Kms2 and the Progression of the Cell Cycle SUN protein Sad1 are involved in anchoring KDP-1 (for KASH-domain protein), which centromeres and heterochromatin at the INM was identiﬁed in a membrane-bound yeast (King et al. 2008). two-hybrid screen with the SUN domain of UNC-84 as bait, localizes to the nuclear envelope in a SUN-1/mateﬁn dependent manner OTHER FUNCTIONS OF KASH (Figure 3h, McGee et al. 2009). Disruption of AND SUN PROTEINS kdp-1 by RNAi causes multiple phenotypes in To this point, we have focused on the structural the early embryo, larvae, and germ line that are roles KASH-SUN bridges play in transferring characteristic of a delay in the cell cycle exiting

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S-phase or entering M-phase (McGee et al. ated with SUN-1/matefin would be ideally sit- 2009). We hypothesize that as a KASH pro- uated in the ONM as a CED-4 receptor. How- tein, KDP-1 is perfectly positioned on the outer ever, no KASH protein has been implicated in Neuromuscular surface of the nuclear envelope to receive a sig- the translocation of CED-4 to the nuclear en- junction (NMJ): a nal from the nucleoplasm that S-phase is com- velope. SUN-1/matefin binds CED-4 in vitro, synapse between the plete and then to relay the message to cdk/cyclin raising the possibility that activated CED-4 en- myotube and the complexes. It will be interesting to see whether ters the nucleoplasm and interacts with SUN- neuron where 3–6 this role in cell cycle regulation is conserved. 1/matefin at the INM (Tzur et al. 2006a). muscle nuclei associate and become transcriptionally specialized WIPs Recruit RanGAP FUNCTIONS OF KASH-SUN to the Outer Nuclear Membrane PROTEINS IN MAMMALS: MOUSE The establishment of a Ran GTP gradient, with MODELS AND HUMAN DISEASES Ran GDP in the cytoplasm, controls the traf- The studies described to this point demon- ficking of soluble proteins between the nucleo- strate that links between the nucleus and the plasm and cytoplasm (Cook et al. 2007, Meier cytoskeleton are essential to a wide variety of et al. 2008). The mammalian nuclear pore com- cellular processes. Because these studies were ponent Nup358/RanBP2 targets RanGAP to carried out in model organisms or tissue cul- the cytoplasmic surface of the pore to ensure ture systems, there are limitations to interpret- that Ran GTP is quickly hydrolyzed to GDP ing how these results relate to human develop- upon exiting the nucleus (Mahajan et al. 1997). ment and disease. Thus, it is gratifying that re- Alternatively, in Arabidopsis RanGAP is targeted cent findings connect SUN and KASH proteins to the ONM by a plant-specific family of in- to human diseases and developmental processes tegral ONM proteins called WIPs (for WP- in mouse models. Mutations in KASH or SUN domain interacting proteins) (Xu et al. 2007). proteins contribute to muscular, neurological, WIP1, 2, and 3 are C-tail-anchored integral skin, and premature-aging disorders. membrane proteins; the C terminus and the transmembrane domain are necessary and sufficient for ONM localization (Xu et al. 2007). Nuclear Positioning in Muscles Although the role of plant SUN proteins has and Muscular Dystrophies not been tested in this process, the WIPs are Mouse Syne/Nesprin-1 and -2 and their likely KASH proteins. partners SUN1 and SUN2 anchor nuclei. In mammalian skeletal muscles, most nuclei

by University of California - Davis on 10/14/10. For personal use only. are evenly spaced throughout the syncytial Recruitment of CED-4 to the Nuclear myotube, whereas 3–6 functionally specialized Envelope to Mediate Apoptosis nuclei are anchored beneath the neuromuscu- Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org During the initiation of programmed cell lar junction (NMJ). Overexpression of either death in C. elegans, the caspase activator and the Syne/Nesprin-1 or -2 KASH domain in proapoptotic factor CED-4 (the Apaf-1 ho- muscles displaces most of the endogenous molog) translocates from the mitochondria Syne/Nesprin-1 and -2 and partially disrupts to the nuclear envelope (Chen et al. 2000); synaptic nuclear clustering (Figure 4b,Grady SUN-1/matefin is required for this process et al. 2005, Zhang et al. 2007b). Mouse knock- (Figure 5c, Tzur et al. 2006a). Further- outs of KASH domain–containing isoforms more, sun-1/matefin(RNAi) embryos have sig- of both genes, individually or simultaneously, nificantly fewer apoptotic events, suggesting provide a more complete understanding of the that the translocation of CED-4 to the nu- functions of Syne/Nesprin-1 and -2 (Zhang clear envelope is an important step in apoptosis et al. 2007b). In Syne/Nesprin-1 but not (Tzur et al. 2006a). A KASH protein associ- Syne/Nesprin-2 single KASH knockouts,

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synaptic and nonsynaptic nuclei are com- et al. 2007a). Syne/Nesprin-1 mutations have pletely unanchored (Zhang et al. 2007b). also been linked to myogenic autosomal Syne/Nesprin-1 and -2 have partially overlap- recessive arthrogryposis, further implicating EDMD: Emery- Dreifuss muscular ping functions because mice lacking both pro- Syne mutations in human muscle pathogenesis dystrophy teins die shortly after birth (Zhang et al. 2007b). (Attali et al. 2009). Laminopathies: a SUN1 single knockout mice have defects in Unlike the Syne/Nesprin-1 KASH knock- broad range of human nuclear anchorage at the NMJ, but SUN1/2 out mouse described in Zhang et al. (2007b), diseases caused by double knockout mice have more severe a second Syne/Nesprin-1 KASH knockout mutations in proteins synaptic nuclear positioning defects as well as mouse is a potential EDMD model. Mice associated with the nonsynaptic nuclear positioning defects and die with this Syne/Nesprin-1 mutation are perinuclear envelope shortly after birth (Lei et al. 2009). Thus, mouse natal lethal, and only approximately half sur- KASH and SUN proteins function in muscle vive birth (Puckelwartz et al. 2009). Surviving development, but the question remains as to mice display EDMD-like phenotypes includ- how they relate to human muscular diseases. ing an abnormal curvature of the spine, mus- Emery-Dreifuss muscular dystrophy cle pathology, and cardiac conduction defects (EDMD) is a neuromuscular condition that develop with age. They also have myonu- characterized by progressive skeletal muscle clear anchorage defects, but Syne/Nesprin-1, degeneration with associated cardiomyopathy SUN2, emerin, and lamin localize normally that originally was found to be caused by (Puckelwartz et al. 2009). These phenotypes mutations in the nuclear-envelope proteins are likely due to a dominant-negative effect emerin or lamin (Bione et al. 1994, Bonne et al. of incorporating mutant Syne/Nesprin-1 into 1999). EDMD is one of a broad spectrum of complexes at the nuclear envelope. Consistent more than 30 diseases known as laminopathies with this, the KASH-SUN interaction is dis- that are caused by mutations in components rupted, indicating that an uncoupling of the of the nuclear envelope (reviewed in Dauer & nucleoskeleton and the cytoskeleton may be Worman 2009, Ellis 2006, Worman & Bonne responsible for the muscle defects (Puckel- 2007). Although the proteins underlying wartz et al. 2009). In the mice in Zhang et al. laminopathies are ubiquitously expressed, (2007b), Syne/Nesprin-1 does not localize to patients develop disease symptoms in a tissue- the nuclear envelope, and there is no lethal- speciﬁc manner. The diseases may be caused ity or EDMD-like phenotypes. The differences by defective nuclei acquiring an increased sen- in these two Syne/Nesprin-1 KASH-deleted sitivity to mechanical stress or a misregulation mutant lines could be explained by the differ- of genes required for development (reviewed in ent mouse backgrounds used to generate the

by University of California - Davis on 10/14/10. For personal use only. Dauer & Worman 2009, Ellis 2006, Worman knockout lines or the different C termini gen- & Bonne 2007). The majority of EDMD erated by the slightly different KASH domain patients do not have mutations in either lamin deletions (Puckelwartz et al. 2009, Zhang et al. Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org or emerin (Bonne et al. 2003). Syne/Nesprin-1 2007b). and -2 interact in vitro with both emerin Lamin A/C or lamin B knockout mice phe- and lamin, and this interaction is altered by nocopy EDMD, have defects in the develop- mutations that cause EDMD (Mislow et al. ment of the central nervous system and the 2002a, Wheeler et al. 2007). Therefore, Syne/ phrenic nerve, and disrupt nuclear positioning Nesprin-1 and -2 may contribute to main- at the NMJ (De Sandre-Giovannoli et al. 2002, taining the integrity of myonuclei during Mejat et al. 2009, Nikolova et al. 2004, Sullivan mechanical stress by forming complexes with et al. 1999, Vergnes et al. 2004). These pheno- emerin and lamin. In support of this hypoth- types are strikingly similar to Syne/Nesprin and esis, Syne/Nesprin-1 and -2 sequence variants SUN knockout mice. Because lamins recruit have been found in EDMD patients that do not SUN proteins to the nuclear envelope, many have either emerin or lamin mutations (Zhang of the defects in lamin knockout mice likely are

434 Starr · Fridolfsson CB26CH17-Starr ARI 3 September 2010 19:43

due to defects in recruiting SUN and KASH 2001, Morris et al. 1998). In these neurons, the proteins to the nuclear envelope. centrosome moves at a constant rate toward the Syne/Nesprin and SUN proteins also leading edge of the cell, whereas the nucleus have signiﬁcant functions in other tissues. moves in a saltatory manner behind it (Bellion The phrenic nerve of the diaphragm in et al. 2005, Schaar & McConnell 2005, Tsai Syne/Nesprin double knockout mice displays et al. 2007). Syne/Nesprin-dependent targeting longer branches than in wild-type mice, sug- of dynein to the nuclear envelope apparently gesting that Syne/Nesprin-1 and -2 mutations pulls on centrosomal microtubules to move the disrupt more than just myonuclear anchorage nucleus (Tsai et al. 2007, Zhang et al. 2009), (Zhang et al. 2007b). Furthermore, the lethality providing a possible link between KASH and of SUN double knockout mice is rescued by ex- SUN proteins and lissencephaly. pressing SUN1 speciﬁcally in neurons (Lei et al. Double knockout mouse lines show that 2009). In these rescued mice, Syne/Nesprin SUN and KASH proteins play essential localization in muscles remains disrupted, in- functions in the nervous system. Loss of either dicating that the lack of muscle functions of SUN1 and SUN2 or Syne/Nesprin-1 and -2 Syne/Nesprin and SUN proteins is not respon- leads to lethality, reduced brain size, malformed sible for the lethality of the knockout mice (Lei cortices, enlarged lateral ventricles, a smaller et al. 2009). corpus callosum, and multiple brain regions with severe laminary defects (Zhang et al. 2009). Syne/Nesprin-2 alone is required for Neuronal Functions proper laminary formation in the hippocampus of SUN-KASH Proteins and cerebral cortex, whereas Syne/Nesprin-1 Syne/Nesprin-1 and -2 play important roles and -2 have redundant roles in other brain in neuronal development. In the developing regions. Although Syne/Nesprin-2 KASH neuroepithelium, nuclear migration events are knockout mice are viable, they have working required for both neurogenesis and neuronal memory defects (Zhang et al. 2009). The migration (reviewed in Baye & Link 2008). laminary defects seen in the cerebral cortex of Neurons proliferate in the neuroepithelium SUN double knockout and Syne/Nesprin-2 while undergoing interkinetic nuclear migra- knockout mice are the result of failed radial tion, during which centrosomes remain at the migrations caused by failure of the nucleus to apical surface, while the nucleus migrates be- migrate (Figure 4c). This is likely due to dis- tween the apical and basal surfaces in conjunc- sociation of the centrosome from the nucleus, tion with cell cycle progression (Frade 2002). which supports the model that Syne/Nesprin

by University of California - Davis on 10/14/10. For personal use only. It has been proposed that dynein moves the proteins couple microtubules to the nucleus nucleus to the apical surface, whereas kinesin through dynein (Zhang et al. 2009). Consistent moves the nucleus toward the basal surface (re- with this, Syne/Nesprin-1 and -2 colocalize Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org viewed in Baye & Link 2008). Syne/Nesprin at the nuclear envelope with dynein (Zhang proteins genetically interact with dynein to et al. 2009). The small brain size in the double move the nucleus during proliferative interki- knockout mice is likely caused by a reduction netic nuclear migration and nuclear positioning in the number of progenitor cells caused events in photoreceptor cells in the develop- by disrupted interkinetic nuclear migration, ing retina of zebraﬁsh (Del Bene et al. 2008, as Syne/Nesprin-2 colocalizes and interacts Tsujikawa et al. 2007). Lissencephaly, a severe with kinesin-1 at the nuclear envelope in the mental retardation disease, is caused by a nu- neuroepithelium (Zhang et al. 2009). clear migration defect in neurons radially mi- Consistent with a role for Syne/Nesprin grating out from the neuroepithelium into the proteins in human neural development, outer layers of the cortex during development Syne/Nesprin-1 mutations cause auto- (reviewed in Lambert de Rouvroit & Gofﬁnet somal recessive cerebellar ataxia type 1

www.annualreviews.org • Nuclear-Cytoskeletal Interactions 435 CB26CH17-Starr ARI 3 September 2010 19:43

(ARCA1) (Gros-Louis et al. 2007). Ataxias are HGPS lamin A/C mutation and may function characterized by a lack of coordination of gait in the prevention of normal aging. and limbs along with neurological symptoms; Progeria: ahuman ARCA1 is late onset (Gros-Louis et al. 2007). disease of premature, SUN-KASH Proteins in Skin rapid aging ARCA1 patients have misplaced nuclei at the NMJ, phenocopying Syne/Nesprin-1 Development, Ciliogenesis, HGPS: Hutchinson- and Cancer Gilford progeria knockout mice (Gros-Louis et al. 2007). The syndrome relationship between this nuclear positioning SUN and KASH proteins are ubiquitously ex- phenotype and the progression of ARCA1 re- pressed in human tissues (Zhang et al. 2001; mains unclear. Dystonia DYT1, a neurological Crisp et al. 2006), and whereas their functions disease of involuntary movements caused by in muscle and neurons are becoming evident, deletion of a single residue in TorsinA (Ozelius what role Syne/Nesprin and SUN proteins have et al. 1999, Tanabe et al. 2009) may also be the in other tissues remains less clear. Nuclear posi- result of disrupted KASH-SUN complexes. tioning in the epidermis is essential for epider- Because TorsinA has been proposed to func- mal stratiﬁcation during development (Lechler tion as a regulator of KASH-SUN interactions, & Fuchs 2005), and mice lacking the largest the role of TorsinA and KASH proteins in isoform of Syne/Nesprin-2 in the skin show a dystonia merits further investigation. thickening of the epidermis (Luke et al. 2008). These mice, which were created by deleting the actin-binding domain of Syne/Nesprin-2, also SUN-KASH Proteins in Aging exhibit epidermal nuclear morphology defects One of the more exciting issues in the ﬁeld is (Luke et al. 2008), which suggests important the role of the nuclear envelope in normal ag- roles for SUN and KASH proteins in skin de- ing and diseases of premature aging. Mutations velopment. in lamin A/C cause multiple laminopathies (re- Meckel-Gruber Syndrome (MKS) is char- viewed in Dauer & Worman 2009, Prokocimer acterized by bilateral renal cystic dysplasia et al. 2009, Worman & Bonne 2007). One, and central nervous system developmental de- Hutchinson-Gilford progeria syndrome fects caused by mutations in genes that con- (HGPS), is characterized by loss of subcu- tribute to building cilia (Kyttala et al. 2006). taneous fat, severe hair loss, restrictive joint Syne/Nesprin-2 is required for ciliogenesis in mobility, bone abnormalities, cardiovascular cell culture, interacts with components of the disease, and progressive arteriosclerosis— primary cilium, and appears to be required for all characteristics of premature aging centrosome migration to the apical cell surface

by University of California - Davis on 10/14/10. For personal use only. (Hennekam 2006). Fibroblasts from HGPS during the early stages of ciliogenesis (Dawe patients and a lamin A/C HGPS-mouse model et al. 2009). In addition, MKS patient cells have altered mechanical properties that lead show a redistribution of Syne/Nesprin-2 and Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org to abnormal nuclear architecture and mor- a reduced centrosome-nucleus distance (Dawe phology (Broers et al. 2004, Dahl et al. 2006). et al. 2009). Thus, SUN and KASH proteins Furthermore, ﬁbroblasts from HGPS mice apparently function in ciliogenesis. have defects in the localization of KASH and Recent studies have linked Syne/Nesprin-1 SUN proteins to the nuclear envelope (Crisp and -2 to cancer. Mutations in Syne/Nesprin- et al. 2006, Libotte et al. 2005). The amount 1 and -2 frequently accumulate in colorec- of Syne/Nesprin-2 at the nuclear envelope is tal and breast cancer tumors, respectively inversely proportional to the HGPS nuclear (Sjoblom et al. 2006). Furthermore, expres- morphology and chromatin organization sion of Syne/Nesprin-1 is downregulated 20– defects (Kandert et al. 2007). This suggests 180-fold in a variety of early tumors (Marme that Syne/Nesprin-2 function at the nuclear et al. 2008). Finally, a large epidemiological membrane offsets the harmful effects of the study found a potential association between a

436 Starr · Fridolfsson CB26CH17-Starr ARI 3 September 2010 19:43

polymorphism in Syne/Nesprin-1 and an in- exciting possibility that KASH and SUN pro- creased risk of invasive ovarian cancer (Doherty teins play roles in cancer progression and there- et al. 2010). Together these studies raise the fore warrant further studies.

SUMMARY POINTS 1. Essential functions of KASH and SUN proteins were initially discovered and characterized by nonbiased forward genetic screens in model yeast and invertebrates. 2. SUN proteins are components of the INM; their N termini interact with the nuclear lamina, and their conserved C-terminal SUN domains extend into the perinuclear space. 3. SUN proteins recruit KASH proteins speciﬁcally to the ONM to complete a bridge across the nuclear envelope. 4. Divergent cytoplasmic domains of KASH proteins mediate interactions with microtubules, centrosomes, and actin ﬁlaments to position nuclei within the cell. 5. KASH-SUN nuclear-envelope bridges also function in meiosis to attach chromosomes to the INM and move them into the bouquet formation, aiding homolog pairing. 6. Mouse knockout studies show that functions of KASH and SUN proteins are conserved from single-cell eukaryotes all the way to mammalian systems, where they play essential roles in neuromuscular development. 7. KASH and SUN proteins have been linked to cancer and implicated in the progression of human diseases including a variety of laminopathies and neurological disorders.

FUTURE ISSUES 1. It remains to be determined how the interactions between KASH and SUN domains are regulated and remodeled during developmental switches, such as between nuclear anchorage and migration. 2. Researchers need to identify the complete array of nucleoplasmic proteins that interact with SUN proteins, cytoplasmic proteins that interact with KASH proteins, and their corresponding functions. by University of California - Davis on 10/14/10. For personal use only. 3. The model that mechanical stimuli are transferred from the outside of the cell directly to chromatin through KASH-SUN bridges needs to be tested.

Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org 4. Researchers need to fully elucidate the mechanisms of how KASH and SUN proteins function in the progression of cancer, laminopathies, and other diseases.

DISCLOSURE STATEMENT The authors are not aware of any afﬁliations, memberships, funding, or ﬁnancial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We apologize to those whose studies were not discussed in detail because of space limitations. We thank E. Tapley and Y.-T. Chang (University of California, Davis), W. Hanna-Rose

www.annualreviews.org • Nuclear-Cytoskeletal Interactions 437 CB26CH17-Starr ARI 3 September 2010 19:43

(Penn State), and D. Hodzic (Washington University) for helpful comments on the manuscript. We thank R. Xu (Fudan University) for sharing unpublished data and R. Xu, W. Hanna-Rose, Y. Hiraoka (Osaka University), M. Alsheimer (Wuezburg University), and Y. Gruenbaum (Hebrew University) for pictures used in the ﬁgures. Our research is supported by grant 5R01GM073874 from the NIH. H.N.F. was supported by NIH training grant 5T32GM007377.

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Contents Annual Review of Cell and Enzymes, Embryos, and Ancestors ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp Developmental John Gerhart 1 Biology

Control of Mitotic Spindle Length Volume 26, 2010 Gohta Goshima and Jonathan M. Scholey pppppppppppppppppppppppppppppppppppppppppppppppppp21 Trafﬁcking to the Ciliary Membrane: How to Get Across the Periciliary Diffusion Barrier? Maxence V. Nachury, E. Scott Seeley, and Hua Jin pppppppppppppppppppppppppppppppppppppppp59 Transmembrane Signaling Proteoglycans John R. Couchman pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp89 Membrane Fusion: Five Lipids, Four SNAREs, Three Chaperones, Two Nucleotides, and a Rab, All Dancing in a Ring on Yeast Vacuoles William Wickner pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp115 Tethering Factors as Organizers of Intracellular Vesicular Trafﬁc I-Mei Yu and Frederick M. Hughson pppppppppppppppppppppppppppppppppppppppppppppppppppppp137 The Diverse Functions of Oxysterol-Binding Proteins Sumana Raychaudhuri and William A. Prinz pppppppppppppppppppppppppppppppppppppppppppp157 Ubiquitination in Postsynaptic Function and Plasticity Angela M. Mabb and Michael D. Ehlers pppppppppppppppppppppppppppppppppppppppppppppppppp179 α-Synuclein: Membrane Interactions and Toxicity in Parkinson’s Disease Pavan K. Auluck, Gabriela Caraveo, and Susan Lindquist pppppppppppppppppppppppppppppp211 by University of California - Davis on 10/14/10. For personal use only. Novel Research Horizons for Presenilins and γ-Secretases in Cell Biology and Disease Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Bart De Strooper and Wim Annaert ppppppppppppppppppppppppppppppppppppppppppppppppppppppp235 Modulation of Host Cell Function by Legionella pneumophila Type IV Effectors Andree Hubber and Craig R. Roy pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp261 A New Wave of Cellular Imaging Derek Toomre and Joerg Bewersdorf ppppppppppppppppppppppppppppppppppppppppppppppppppppppp285 Mechanical Integration of Actin and Adhesion Dynamics in Cell Migration Margaret L. Gardel, Ian C. Schneider, Yvonne Aratyn-Schaus, and Clare M. Waterman pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp315

vii AR425-FM ARI 14 September 2010 18:54

Cell Motility and Mechanics in Three-Dimensional Collagen Matrices Frederick Grinnell and W. Matthew Petroll ppppppppppppppppppppppppppppppppppppppppppppppp335 Rolling Cell Adhesion Rodger P. McEver and Cheng Zhu ppppppppppppppppppppppppppppppppppppppppppppppppppppppppp363 Assembly of Fibronectin Extracellular Matrix Purva Singh, Cara Carraher, and Jean E. Schwarzbauer pppppppppppppppppppppppppppppppp397 Interactions Between Nuclei and the Cytoskeleton Are Mediated by SUN-KASH Nuclear-Envelope Bridges Daniel A. Starr and Heidi N. Fridolfsson ppppppppppppppppppppppppppppppppppppppppppppppppp421 Plant Nuclear Hormone Receptors: A Role for Small Molecules in Protein-Protein Interactions Shelley Lumba, Sean R. Cutler, and Peter McCourt pppppppppppppppppppppppppppppppppppppp445 Mammalian Su(var) Genes in Chromatin Control Barna D. Fodor, Nicholas Shukeir, Gunter Reuter, and Thomas Jenuwein pppppppppppppp471 Chromatin Regulatory Mechanisms in Pluripotency Julie A. Lessard and Gerald R. Crabtree ppppppppppppppppppppppppppppppppppppppppppppppppppp503 Presentation Counts: Microenvironmental Regulation of Stem Cells by Biophysical and Material Cues Albert J. Keung, Sanjay Kumar, and David V. Schaffer pppppppppppppppppppppppppppppppppp533 Paramutation and Development Jay B. Hollick pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp557 Assembling Neural Crest Regulatory Circuits into a Gene Regulatory Network Paola Betancur, Marianne Bronner-Fraser, and Tatjana Sauka-Spengler ppppppppppppppp581 Regulatory Mechanisms for Speciﬁcation and Patterning of Plant

by University of California - Davis on 10/14/10. For personal use only. Vascular Tissues Ana Ca˜no-Delgado, Ji-Young Lee, and Taku Demura pppppppppppppppppppppppppppppppppppp605

Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Common Factors Regulating Patterning of the Nervous and Vascular Systems Mariana Melani and Brant M. Weinstein ppppppppppppppppppppppppppppppppppppppppppppppppp639 Stem Cell Models of Cardiac Development and Disease Kiran Musunuru, Ibrahim J. Domian, and Kenneth R. Chien pppppppppppppppppppppppppp667 Stochastic Mechanisms of Cell Fate Speciﬁcation that Yield Random or Robust Outcomes Robert J. Johnston, Jr. and Claude Desplan pppppppppppppppppppppppppppppppppppppppppppppppp689 A Decade of Systems Biology Han-Yu Chuang, Matan Hofree, and Trey Ideker pppppppppppppppppppppppppppppppppppppppp721

viii Contents